Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), agents that convert the proenzyme plasminogen to the fibrinolytic enzyme plasmin. Regulation of fibrinolysis by PAI-1 is an important control point for normal vascular function, as the accumulation of fibrin can lead to blood clots, while an excessive decrease in fibrin can lead to hemorrhage. PAI-1 also plays an important role in tissue fibrosis by inactivating matrix metalloproteinases as well as plasmin generation (Takeshita, K, et al., American Journal of Physiology, 2004(2):449-456), and studies that modulated PAI-1 expression in animal models have implicated PAI-1 in the pathogenesis of fibrosis after chemical or immune-mediated injury (Weisberg. A D et al., Arterioscler. Thromb. Vasc. Biol., 2005, 25:365-371).
PAI-1 has also been implicated in the pathophysiology of renal, pulmonary, cardiovascular, and metabolic diseases (Cale, J M and Lawrence, D A. Curr Drug Targets, 2007, 8(9):971-81), as well as cancer. A number of investigations have supported a role for PAI-1 in the development of heart disease. For example, pharmacologic inhibition of PAI-1 was demonstrated to protect against antiotensin-II-induced aortic remodeling (Weisberg. A D et al., Arterioscler. Thromb. Vasc. Biol., 2005, 25:365-371). Further, attenuated development of cardiac fibrosis was observed in PAI-deficient mice after myocardial infarction compared to wild-type (Takesita, K, et al., American Journal of Pathology, 2004, 164(2):449-455. Several studies (reviewed in Sobel, B E et al., Arterioscler. Thromb. Vasc. Biol., 2003, 23:1979-1989) suggest altered expression of PAI-1 in vessel walls might contribute to coronary atherogenesis.
New reagents and methods for manipulating PAI-1 expression in heart would advance research into its role in heart disease. Further, there is a need in this area for novel reagents, treatments, and methods for inhibiting PAI-1 activity.